PROJECT SUMMARY Stroke is a major public health problem in the U.S. and worldwide. It is defined as an area of brain damage, generally due to the sudden occlusion of an artery in or leading to the brain. Stroke can cause weakness, numbness, visual disturbance, speech difficulty, balance problems, and memory loss, among other symptoms. While good treatments exist to limit stroke in the first few hours after occurrence, few treatments exist to improve neurological recovery from deficits remaining after such acute treatments. Although physical, occupational, and speech therapy are useful, no new drugs have been approved that promote stroke recovery. We showed in previous studies that the intracerebral administration of fibroblast growth factor-2 (FGF-2) enhances neurological recovery after experimental stroke in rats, most likely through stimulation of neuronal sprouting and progenitor cell proliferation in brain. However, FGF-2 is a charged protein that is difficult to administer systemically as a drug. More recently, we have identified a small molecule, STMX228, which binds to FGF-2 complexed to its major receptor FGFR1, and increases biological signaling of this complex. Like FGF-2, STMX228 enhances stroke recovery in rats, including adult males and females, as well as aged rats. However, STMX228 itself is not suitable as a drug candidate, because of poor solubility and other factors. The current proposal seeks to identify one or more druglike analogs of STMX228, and to subject the most promising of these to further detailed characterization. Analogs of STMX228 will be chemically generated and run through a complex eight-stage in vitro and in vivo vetting process designed to select and characterize the most promising drug candidates. We expect that the proposed studies will generate a single ?lead? compound as well as backups that are suitable for further development as stroke recovery-promoting drugs in humans.